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Angiotensin Receptor Type I Blockade Inhibits Apoptosis in Meconium-Instilled Rabbit Lungs

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DOI: 10.4236/jct.2011.25084    2,841 Downloads   5,127 Views   Citations

ABSTRACT

Background and objectives: In prior studies we demonstrated that meconium-induced lung cell death by apoptosis was associated with activation of the local pulmonary renin-angiotensin system (RASL). Alveolar epithelial apoptosis requires the authocrine synthesis and proteolytic processing of angiotensinogen (AGT) to Angiotensin II (ANG II). Inhibitors of angiotensin converting enzyme (ACE) block meconium-induced apoptosis. ANG II plays an essential role in vascular homeostasis and lung injury. The objectives of this study were to evaluate expression of AGT, ANG II and Caspase 3 in meconium and saline treated newborn lungs and to study mechanisms of its inhibition by a selective antagonist of the AT1 receptor. Methods: Two week old rabbits were studied. Three treatment groups were studied (six rabbit pups in each group): Group 1: rabbits instilled with saline; Group 2: rabbits instilled with 10% meconium; Group 3: Losartan pretreated followed by meconium-instillation. Three groups of A549 human lung epithelial cells were studies as well. Group 4: AGT pretreated and then meconium-exposed cells; Group 5: ANG II pretreated and then meconium exposed cells and Group 6: Caspase 3 inhibitor ZVAD-fmk pretreated and then meconium exposed cells. AGT, ANG II and Caspase 3 were evaluated and compared with and without inhibitors in meconium and control groups. Results: In Situ End Labeling (ISEL) and Caspase 3 assays showed that purified ANG II induced dose dependent apoptosis in rabbit lung lavage cells and the human A549 lung epithelial cell line. Apoptosis also was induced by purified AGT. The increase in apoptotic cells was accompanied by increases in ANG II and Caspase 3 activities. In both airway epithelium and alveolar wall cells, measures of apoptosis were attenuated by Losartan or by the Caspase 3 inhibitor ZVAD-fmk. Conclusions: These data demonstrate the presence of a functional ANG II and Caspase 3 dependent apoptotic pathways in newborn meconium-instilled lungs. They also imply that meconium-induced apoptosis is modulated by the pulmonary RASL system in which ANG II plays a critical role. Both losartan and the Caspase 3 inhibitor ZVAD-fmk pretreatment significantly decreased meconium-induced Caspase-3 activation and lung cell apoptosis.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

A. Zagariya, S. Navale, B. Uhal, O. Zagariya and D. Vidyasagar, "Angiotensin Receptor Type I Blockade Inhibits Apoptosis in Meconium-Instilled Rabbit Lungs," Journal of Cancer Therapy, Vol. 2 No. 5, 2011, pp. 629-637. doi: 10.4236/jct.2011.25084.

References

[1] S. Kauffman, “Cell proliferation in the Mammalian Lung,” International Review of Experimental Pathology, Vol. 22, 1980, pp. 131-191.
[2] R. Mason and M. Williams, “Type II Alveolar Epithelial Cells,” In: R. G. Crystal and J. B. West, Eds., The Lung: Scientific Foundations, Raven, New York, 1991, pp. 235-246.
[3] A. Zagariya, R. Bhat, B. Uhal, et al., “Cell Death and Lung Cell Histology in Meconium Aspirated Newborn Lungs,” European Journal of Pediatrics, Vol. 159, No. 11, 2000, pp. 819-826. doi:10.1007/s004310000581
[4] E. White, “Life, Death and the Pursuit of Apoptosis,” Genes & Development, Vol. 10, No. 1, 1996, pp. 1-15. doi:10.1101/gad.10.1.1
[5] R. Wang, G. Alam, A. Zagariya, et al., “Apoptosis of Lung Epithelial Cells in Response to TNFα Requires Angiotensin II Generation de novo,” Journal of Cellular Physiology, Vol. 185, No. 2, 2000, pp. 253-259. doi:10.1002/1097-4652(200011)185:2<253::AID-JCP10>3.3.CO;2-R
[6] A. Zagariya, S. Mungre, R. Lovis, et al., “Tumor Necrosis Factor Alpha Gene Regulation: Enchantment of C/ EBP?—Induced Activation by c-Jun,” Molecular and Cellular Biology, Vol. 18, No. 5, 1998, pp. 2815-2824.
[7] R. Wang, A. Zagariya, E. Ang, et al., “FAS-Induced Apoptosis of Alveolar Epithelial Cells Requires ANG II Generation and Receptor Interaction,” American Journal of Physiology, Vol. 277, No. 6, 1999, pp. L1245-1250.
[8] R. Wang, C. Ramos, I. Joshi, et al., “Human Lung Myofibroblast-Derived Inducers of Alveolar Epithelial Apoptosis Identified Angiotensin Peptides,” American Journal of Physiology, Vol. 277, No. 6, 1999, pp. L1158-1164.
[9] D. Munzenmaier, “Greene Opposite Actions of Angiotensin II on Microvascular Growth and Arterial Blood Pressure,” Hypertension, Vol. 27, 1996, pp. 760-766.
[10] T. Yamada, M. Horiuchi and V. Dzau, “Angiotensin Type 2 Receptor Mediates Programmed Cell Death,” Proceedings of the National Academy of Sciences, Vol. 93, No. 1, 1996, pp. 156-160. doi:10.1073/pnas.93.1.156
[11] S. Kumar, “ICE-Like Proteases in Apoptosis,” Trends in Biochemical Sciences, Vol. 20, No. 5, 1995, pp. 198-202. doi:10.1016/S0968-0004(00)89007-6
[12] D. Nicholson, A. Ali, N. Thornberry, et al., “Identification and Inhibition of the ICE/CED-3 Protease Necessary for Mammalian Apoptosis,” Nature, Vol. 376, No. 6535, 1995, pp. 37-43. doi:10.1038/376037a0
[13] L. Harrison-Bernard, L. Navar, H. Ho, G. Vinson and S. El-Dahr, “Immunohistochemical Localization of ANG II AT1 Receptor in Adult Rat Kidney Using a Monoclonal Antibody,” American Journal of Physiology, Vol. 273, No. 1, 1999, pp. F170-F177. doi:10.1097/00004872-199816010-00014
[14] R. Wang, A. Zagariya, O. Ibarra-Sunga, et al., “Angiotensin II Induced Apoptosis in Human and Rat Alveolar Epithelial Cells,” American Journal of Physiology, Vol. 276, No. 5, 1999, pp. L885-L889.
[15] K. Lai, J. Leung, W. To, et al., “Gene Expression of the Rennin Angiotensin System in Human Kidney,” Journal of Hypertension, Vol. 16, No. 1, 1998, pp. 91-102.
[16] P. Ponte, S. Ng, J. Engel, et al., “Evolutionary Conservation Is in the Untranslated Regions of Actin mRNAs: DNA Sequence of a Human ?-actin cDNA,” Nucleic Acids Research, Vol. 12, 1984, pp. 1687-1696. doi:10.1093/nar/12.3.1687
[17] S. Dimmeler, U. Rippmann, J. Weiland, et al., “Angiotensin II Induces Apoptosis of Human Endothelial Cells,” Circulation Research, Vol. 81, No. 6, 1996, pp. 970-976.
[18] J. Kajstura, A. Cigola, P. Malhotra, et al., “Angiotensin II Induces Apoptosis of Adult Ventricular Myocytes in Vitro,” Journal of Molecular and Cellular Cardiology, Vol. 29, No. 3, 1997, pp. 859-870.
[19] S. Dimmeler, S. Brinkmann and E. Neugebauer, “Endotoxin-Induced Changes of Endothelial Cell Viability and Permeability: Protective Effect of a 21-Aminosteroid,” European Journal of Pharmacology, Vol. 287, No. 3, 2005, pp. 257-261. doi:10.1016/0014-2999(95)00499-8
[20] B. Grasp-Kraup, H. Ruttkay-Nedecky, H. Koudelka, et al., “In Situ Detection of Fragmented DNA Fails to Discriminate among Apoptosis, Necrosis and Autolytic Cell Death: A Cautionary Note,” Hepatology, Vol. 21, No. 5, 1995, pp. 1465-1468.
[21] F. Lyall, F. Dornan, J. McQuen, et al., “Angiotensin II Increases Protooncogene Expression and Phosphoinisitide Turnover in Vascular Smooth Muscle Cells via the Angiotensin II AT1 Receptor,” Journal of Hypertension, Vol. 10, No. 1, 1992, pp. 1463-1469. doi:10.1097/00004872-199210120-00005
[22] H. Oskarsson and D. Heistad, “Oxidative Stress Produced by Angiotensin Too: Implications for Hypertension and Vascular Disease,” Circulation, Vol. 95, 1997, pp. 557- 559.
[23] M. Jacobson, “Reactive Oxygen Species and Programmed Cell Death,” Trends in Biochemical Sciences, Vol. 21, No. 3, 1996, pp. 83-86.
[24] R. Ross, “Cell Biology of Atherosclerosis,” Annual Review of Physiology, Vol. 57, 1995, pp. 791-804. doi:10.1146/annurev.ph.57.030195.004043
[25] F. Cambien, O. Poirier, L. Lecerf, et al., “Deletion Polymorphism in the Gene for Angiotensin-Converting Enzyme Is a Potential Risk Factor for Myocardial Infarction in Patients with Hypertention,” New England Journal of Medicine, Vol. 324, 1992, pp. 1098-1104.

  
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